Project Summary. During the last phase of this project, we developed new tools to discover mobile element insertions (MEIs) in human genomes on a population-scale and then used these tools to generate the final MEI call sets for the 1000 Genomes Project. During the next phase of this competitive renewal, we now propose to build upon these initial successes to perform MEI discovery on an even larger scale. In Aim 1 we propose to perform population-scale MEI discovery and analysis in collaboration with several large consortia. Through collaborations with the Simons Foundation Autism Consortium, the TOPMed project, and other projects, we will perform MEI discovery in ~94,000 genomes and exomes. These studies will allow us to examine the impact of MEIs on human traits and diseases on a much larger scale than has been examined previously. In Aim 2 we will study the full-length L1 (FL-L1) source elements that generate MEIs in humans. We will develop a comprehensive resource of FL-L1 elements using PacBio-based sequencing approaches. We will then use this resource to study how MEI genesis varies in diverse human genomes and populations. Finally, in Aim 3 we will leverage the unique resources that we will generate in Aims 1 and 2 of this project to study the rates of de novo MEI formation in families and extended pedigrees. These studies involve large resources of diverse families and pedigrees (including European, African American, East Asian, and Hispanic families and pedigrees), which also provides us with a unique opportunity to compare the relative rates of de novo MEI production across diverse populations. We hypothesize that MEI production rates will vary among diverse populations due to differences in FL-L1 source content. We will continue to test this hypothesis in Aim 3. This project will potentially have a sustained and significant impact on the human genetics community by facilitating MEI detection on a broad scale for the first time.